DESCRIPTION (applicant's abstract): The major objective of this research program is to facilitate novel drug development for G-Protein Coupled Receptors (GPCRs) using high throughput screening (HTS) protein structure-based drug design (SBDD). GPCRs are integral membrane proteins found ubiquitously in human tissues, and are associated with many diseases. The primary focus of this SBDD effort will be based on engineered, soluble, N-terminal extracellular domain analogs of GPCRs. Many GPCRs use a large N-terminal domain as an essential ligand-binding component. Use of these analogs in drug discovery will eliminate the need for detergents and lipids that often complicate HTS and SBDD efforts for GPCRs.In Phase I we constructed a novel, soluble, N-terminal domain analog of the glucagon receptor (N-GGR). Characterization of N-GGR revealed that about80 percent of the binding free energy for glucagon resides within this domain. Importantly, N-GGR discriminates against the related peptide, GLP- 1, and competes with full-length GGR in functional assays. During the Phase II we will determine the X-ray crystal structure of N-GGR and use it as an HTS target for drug discovery. We will also validate N-GGR as a protein therapeutic. In Phase III we will optimize small molecule leads into potential drugs ready for in vivo pre-clinical and clinical testing. PROPOSED COMMERCIAL APPLICATION: Not Available